CN104755082A - Prophylactic and/or therapeutic agent for behavioral and psychological symptoms associated with neurodegenerative disease or impulsive symptoms associated with mental disease containing brexpiprazole or salt thereof - Google Patents

Prophylactic and/or therapeutic agent for behavioral and psychological symptoms associated with neurodegenerative disease or impulsive symptoms associated with mental disease containing brexpiprazole or salt thereof Download PDF

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Publication number
CN104755082A
CN104755082A CN201380055961.6A CN201380055961A CN104755082A CN 104755082 A CN104755082 A CN 104755082A CN 201380055961 A CN201380055961 A CN 201380055961A CN 104755082 A CN104755082 A CN 104755082A
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prevent
disorder
treat
syndrome
dementia
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佐藤慎二
前田健二
石川大
中村舞
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Otsuka Pharmaceutical Co Ltd
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Otsuka Pharmaceutical Co Ltd
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Priority to CN202011339120.6A priority Critical patent/CN112402421A/en
Priority to CN201810366157.4A priority patent/CN108578408A/en
Priority to CN202210498926.2A priority patent/CN114712360A/en
Publication of CN104755082A publication Critical patent/CN104755082A/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Abstract

The present invention relates to a prophylactic and/or therapeutic agent for behavioral and psychological symptoms associated with neurodegenerative disease or impulsive symptoms associated with mental disease, which contains 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof as an active ingredient.

Description

Agent is prevented and/or treated for the behavioral and psychiatric symptoms relevant to neurodegenerative disease or the impulsion symptom of being correlated with mental sickness containing epirizole group or its salt
Technical field
The present invention relates to a kind of send (Brexpiprazole) or its salt containing epirizole prevent and/or treat agent for the behavioral and psychiatric symptoms relevant to neurodegenerative disease or the impulsion symptom of being correlated with mental sickness.
Background technology
Epirizole is sent (OPC-34712), i.e. 7-[4-(4-benzo [b] thiophene-4-base-piperazine-1-base) butoxy]-1H-quinoline-2-one-, or its salt and production method thereof are described in patent documentation 1 (JP-A-2006-316052 (US 2010/0179322 A1)), and be described to that there is dopamine D 2acceptor portion agonist activity (D 2acceptor portion agonist is active), serotonin 5-HT 2Areceptor antagonist activity (5-HT 2Areceptor antagonist activity) and adrenergic α 1receptor antagonist activity (α 1receptor antagonist activity), and, in addition, there is serotonin picked-up inhibitory action (or serotonin reuptake inhibition) simultaneously, and for central nervous diseases, there is wide treatment spectrum.Although this patent documentation describes epirizole group or its salt pair cognitive impairment relevant to neurodegenerative disease (such as Alzheimer etc.) is useful, the completely not mentioned behavioral and psychiatric symptoms for neurodegenerative disease or the impulsion symptom relevant to mental sickness whether useful.
In addition, this patent documentation do not describe epirizole group or its salt significantly strengthen in prefrontal cortex (ACA: front cingulate area (Anterior cingulate area), PL: proparea, edge (Prelimbic area), IL: edge inferior segment (Infralimbic area)) activity.
Someone report in relevant (the Bipolar Disord 2009 of impulsion symptom of the activity reduction of prefrontal cortex and the behavioral and psychiatric symptoms of neurodegenerative disease and mental sickness; 11:628-36, J Abnorm Psychol 2013; 122:558-65, MovDisord 2011; 26:225-33, Pharmacol Biochem Behav 2009; 93:237-47).
Impulsion symptom belongs to the multiple personality traits of the various actions characterizing people, and its promotion is caused by central nervous diseases (that is, mental sickness, neurodegenerative disease etc.) usually, and closely related with violence, aggression, suicide etc.According to the definition of Impulsive bio-psycho sociology, Impulsive be defined as a kind of to inner or outside stimulation towards not considering tendency (the Am JPsychiatry 2001 of these reactions for the individuality of impulsion or the negative results for other people fast, without plan reaction; 158:1783 – 93).In addition, based on three Impulsive subscales that are Impulsive by attention, behavior, that produce due to cause Impulsive etc. of shortage plan, the Impulsive scale of Barratt (Impulsivity Scale) can Impulsive characteristic (the J Clin Psychol 1995 that has of evaluator; 51:768 – 74).
The example with the mental sickness of impulsion symptom comprises schizophrenia, major depression, bipolar disorder, attention deficit hyperactivity disorder (AD/HD), autism, antisocial personality disorder, borderline personality disorder, drug dependence/dependence syndrome etc.
Although many schizophrenics do not show violent behavior, a part of patients goes out lasting aggression, and sometimes hinders dispenser or make care-giver have burden.1973-2006 is in the longitudinal epidemiologic that Sweden carries out is studied, and the crowd of 5.3% involves violent crime; And the schizophrenic of 13.2% involves violent crime (JAMA 2009; 301:2016 – 23).The cause of the violent behavior in schizophrenic patients has discordance, and it is considered to derive from the i) positive symptom, such as hallucination-vain hope etc., ii) Impulsive, iii) concurrency psychopathia (Int J Clin Pract 2008; 62:1237 – 45).
The people such as Citrome use clozapine, olanzapine, risperidone and haloperidol to have studied aggressivity inhibitory action (the Psychiatric Services 2001 of existing antipsychotic drug to schizophrenic by perspective random double blind test (prospective randomized double-blind trial); 52:1510 – 14).In order to assess, use one of positive scale of PANSS (Positive and Negative Symptom Scale, Positive and Negative Symptom Scale), hostility.Clozapine only weakens hostility statistically significantly, and on the other hand, risperidone and haloperidol increase the weight of hostility.Olanzapine only shows minimum improvement result.Because the hostility display effect to a certain degree of Clozapine with schizophrenic patients, so the schizophrenic of display violent behavior is recommended to take it.But clozapine is a kind of antipsychotic drug with extremely strong effect, and its effect can be suppress violent behavior by improving the above-mentioned i) positive symptom.Not yet confirm whether can suppress to come from ii) Impulsive violent behavior.In addition, because clozapine causes serious side effect, as agranulocytosis etc., so limit the medical institutions and patient that can use this medicine.
Have the report more than 100 parts of genes relevant to schizophrenia onset, these reports are based on the analysis etc. of pedigree analysis, gene pleiomorphism.Wherein, schizophrenia fracture 1 (Disrupted-In-Schizophrenia 1, the Disc1) gene with No. 1 chromosome and No. 11 chromosomal mutual transpositions found in Scottish schizophrenia extended familys arouses attention as causing schizoid predisposing factor.There is the mice display Schizophreniform Deviant Behavior of Disc1 L100P site mutation, and the antipsychotic drug as clozapine and haloperidol decrease as described in Schizophreniform behavior.In addition, the reduction of cranial capacity and biochemical analysis have shown its use (Neuron 54 (3): 387-402,2007) as Schizophreniform model.
Major depression and suicidal tendency closely related, and symptom of getting excited is considered to its important predictor (Am JPsychiatry 1999; 156:181 – 89).The patient suffering from major depression more to get excited (Am J Psychiatry2005 than Healthy People; 162:1680 – 7), and be easier to suicidal attempt and suicide (Prog Neuropsychopharmacol BiolPsychiatry 2003; 27:829-33, Epidemiol Psichiatr Soc 2009; 18:172-8).As selective serotonin reuptake inhibitor (the selective serotonin re-uptake inhibitor of antidepressant, SSRI) relation increased with suicide risk is noted, and antidepressant is taken warning in 2004 by FDA (FDA) can cause the activation syndrome (activation syndrome, AS) that may cause committing suiside.There is in the outpatient opening antidepressant prescription the retrospective survey that AS carries out 3 months in the people such as Harada, and finds that 4.3% in them show AS (Depress Anxiety 2008; 25:1014-9).Therefore, when there is AS after take antidepressant under clinical setting, be difficult to determine whether the side effect of antidepressant or the deterioration of present illness, and doctor is difficult to judge whether to continue to take antidepressant usually.Therefore, the major depression patient for having high impulsion symptom is needed to set up suitable therapy.
About the violent behavior in bipolar disorder, the people such as Barlow have issued report (Aust N Z J Psychiatry2000; 34:967-74).Bipolar disorder patients under the research display manic state of 1269 inpatients suffering from mental sickness more than 18 months is shown to the violent behavior of highest ratios ratio (odds ratio).In addition, most of violent behavior is considered to obviously be caused by Impulsive, and many violent behavior occur with maniac access.
Clinically, the treatment of prescription for maniac access of mood stabilizer and antipsychotic drug is opened.Although the effectiveness of described prescription reports (Arch Gen Psychiatry 2007 by meta-analysis (meta-analysis); 64:442-55, ActaPsychiatr Scand 2007; 115:12-20), but also there is not the test studying described violent behavior at present.
Alcohol dependence and drug dependence are relevant to ethanol and the medicine mental sickness meeting some diagnostic criterias (such as resist, thirst for, withdrawal symptom etc.).As everyone knows, dependence syndrome patient takes impulsive behavior.They not only can not suppress the absorption behavior of ethanol and medicine, and needed for they take quick behavior to meet at once, although it can cause bad result in future.So, patient usually can crime, as violent behavior etc.Allegedly this impulsive behavior (Pharmacol Biochem Behav 2009 relevant to prefrontal cortex obstacle; 93:237-47).In order to treat alcohol dependence, open opioid antagonist (as naltrexone and nalmefene) prescription inhibit one's impulses drink and help control Ethanol intake.But its therapeutic effect is not enough, and need to set up medicament and Therapeutic Method that higher therapeutic effect is provided.
The example of neurodegenerative disease comprises dementia [dementia of the Alzheimer type (Alzheimer-type dementia, AD), dementia with Lewy body (dementia with Lewy bodies), Parkinson dementia (Parkinson ' s type dementia), Frontotemporal dementia (frontotemporal dementia), vascular dementia (cerebrovascular dementia), Huntington Chorea (Huntington ' s disease)], multiple sclerosis etc.
The example of the behavioral and psychiatric symptoms in neurodegenerative disease comprises dull-witted etc. behavioral and psychiatric symptoms.
Dementia is divided into " core symptom " that mainly show cognitive impairment (as memory, orientation, discernment etc.), and is " behavioral and psychiatric symptoms " of mental symptom and the symptom of getting excited be associated with " core symptom ".Mental symptom comprises depression, anxiety, hallucination, vain hope, sleep disorder etc., and symptom of getting excited comprises violence, violence language, absentminded, refusal, unclean behavior etc.In the nineteen ninety-five international psychogeriatrics association (International PsychogeriatricAssociation) that holds of the U.S., these behavior disorders are defined as " in dementia patients frequent occur perception of obstacles, thought content, emotion or behavior symptom ", and be after this called as BPSD (dull-witted behavioral and psychiatric symptoms (Behavioral andPsychological Symptoms of Dementia)).
According to epidemiological study, the dementia patients of being in of 80% shows dystropy, that is, BPSD, and more often occurs BPSD when dementia develops into moderate from slight extent.Because home care becomes difficulty gradually, the QOL (quality of life) of patient and care-giver significantly reduces.Relatively slight BPSD sometimes can by " non-drug therapy " process, and it comprises suitably betters people's living environment and nurse.But, more than degree is medium and there is (e.g., the not only pressure increase etc. of patient but also care-giver) in various problem time, all need Drug therapy in many cases.
About Alzheimer, it is a kind of typical neurodegenerative disease, there is a donepezil to the research report (N Engl J Med 2007,357:1382-1392) of the therapeutic effect of 12 weeks of exciting (it is the one in behavioral and psychiatric symptoms).The patient suffering from very serious Alzheimer taken care of in sanatorium is divided into placebo group and donepezil administration group, and tests.By CMAI (the challenges questionnaire of Cohen-Mansfield (AgitationInventory)) and NPI (psychoneural questionnaire (Neuropsychiatric Inventory)), they are assessed.As a result, each score is presented between placebo group and donepezil administration group does not have statistically significant difference, and this score display itself does not almost change (p value: CMAI 0.98, NPI 0.95).This result can be interpreted as meaning that donepezil does not improve or promotes excitement.Therefore, donepezil is a kind of medicament of expecting the cognitive function improved in Alzheimer, but it does not show improvement result on the behavioral and psychiatric symptoms (especially exciting) often increasing burden of caregiver.
The people such as Alexander report a kind of BPSD model (Behavioural Brain Research 2011 being recorded to attack by using Tg2576 mice (one in its AD model mice being whole world use); 216:77 – 83).Tg2576 has the AD model mice that Sweden and London type amyloid precursor protein (Amyloid Precursor Protein, APP) suddenly change.In this model of application settler-invader's test method(s), the A/J mice (invader) without aggressivity pedigree is made to invade the cage of the Tg2576 (settler) fed separately.Study the aggressivity of 7 months large Tg2576.First time attacks the time remarkable reduction compared with control mice needed, and the attack quantity of 10min significantly increases.
In addition, the people such as Vloeberghs report based on APP23 mice night physiological rhythm change (the Eur J Neurosci 2004 of amount of autonomic movement behavior; 10:2757-66).APP23 mice is the AD model mice with Sweden APP sudden change.Contrast 12 months large APP23 mices and wild-type mice 3 days.As a result, the autonomic movement behavior of wild-type mice is only high at the night of initial day, and significantly reduces on the 2nd and the 3rd.On the other hand, APP23 mice shows the high growth of the autonomic movement behavior at 3 nights., APP23 mice compares remarkable increase the 2nd with the autonomic movement behavior of the 3rd day with the autonomic movement behavior at the 3rd day night and wild-type mice the 2nd.
As what confirm in the above-mentioned report mentioned, have the research report of the AD model mice of many display sections BPSD symptom, and the medicine using the autonomic movement behavior of the attack of these model mices and promotion to research and develop for BPSD as index becomes possibility.
The feature of dementia with Lewy body (DLB) is optical illusion and audition hallucination, and Progressive symmetric erythrokeratodermia cognitive impairment and the parkinson disease sample dyskinesia two kinds all occur as symptom.In senile degenerative dementia obstacle, it is common inferior to second of dementia of the Alzheimer type.DLB is a kind of from the early stage just the most normal dementia with BPSD, and therefore, the significantly QOL of infringement patient and tender.The people such as Fujita are recorded to the gene mutation found in familial DLB, and successfully generate novel transgene mouse model (the Nat Commun 2010 expressing saltant type P123H β-synapse nucleoprotein; 1:110).This mice also shows cognitive symptom except various pathological findings, and shows BPSD-sample Deviant Behavior further.Therefore, by using this model mice also can research and develop medicine for BPSD.
As mentioned above, once develop the behavioral and psychiatric symptoms relevant to neurodegenerative disease or the impulsion symptom relevant with mental sickness, extremely heavy burden will be increased to care-giver, and the people of surrounding may be injured.Therefore, the medicament suppressing these symptoms is needed.
Summary of the invention
The object of this invention is to provide one and prevent and/or treat agent, its in safety to the behavioral and psychiatric symptoms relevant to neurodegenerative disease or and the mental sickness impulsion symptom of being correlated be excellent.
In order to solve the problem, the present inventor has used the attack of AD model mice with app gene sudden change and the autonomic movement behavior etc. of promotion to conduct in-depth research as index, and finds that epirizole group or its salt pair behavioral and psychiatric symptoms relevant to neurodegenerative disease or the impulsion symptom of being correlated with mental sickness are effective.In addition, their neurocyte of the closely-related middle prefrontal cortex of impulsion symptom of having been found that epirizole group or its salt activator and the behavioral and psychiatric symptoms relevant to neurodegenerative disease and being correlated with mental sickness.
The invention provides and a kind ofly prevent and/or treat agent for the behavioral and psychiatric symptoms relevant to neurodegenerative disease or the impulsion symptom of being correlated with mental sickness, it contains epirizole group or its salt as active component.
The invention provides a kind of for the behavioral and psychiatric symptoms relevant to neurodegenerative disease or the compositions (pharmaceutical composition) prevented and/or treated of impulsion symptom of being correlated with mental sickness, it contains epirizole group or its salt as active component.
The invention provides epirizole group or its salt for the production of for the behavioral and psychiatric symptoms relevant to neurodegenerative disease or the purposes preventing and/or treating agent of impulsion symptom of being correlated with mental sickness.
What the invention provides a kind of behavioral and psychiatric symptoms relevant to neurodegenerative disease or the impulsion symptom of being correlated with mental sickness prevents and/or treats method, and its patient comprising the impulsion symptom preventing and/or treating the behavioral and psychiatric symptoms relevant to neurodegenerative disease to needs or be correlated with mental sickness uses the epirizole preventing or treat effective dose to be sent or its salt.
What the invention provides a kind of behavioral and psychiatric symptoms relevant to neurodegenerative disease or the impulsion symptom of being correlated with mental sickness prevents and/or treats method, it comprises, in the patient of impulsion symptom needing to prevent and/or treat the behavioral and psychiatric symptoms relevant to neurodegenerative disease or be correlated with mental sickness, the epirizole group that the medicine to usually available antipsychotic drug or neurodegenerative disease fails to provide the patient of sufficient effect to use prevention or treatment effective dose or its salt.
That is, the invention provides a kind of in following items 1 to 59 display prevent and/or treat agent for the behavioral and psychiatric symptoms relevant to central nervous diseases.
Project 1
The behavioral and psychiatric symptoms relevant to neurodegenerative disease or the impulsion symptom of being correlated with mental sickness prevent and/or treat a method, its patient comprising the impulsion symptom preventing and/or treating the behavioral and psychiatric symptoms relevant to neurodegenerative disease to needs or be correlated with mental sickness uses 7-[4-(4-benzo [b] thiophene-4-base-piperazine-1-base) the butoxy]-1H-quinoline-2-one-or its salt that prevent or treat effective dose.
Project 2
As described in project 1, prevent and/or treat method, its be a kind of behavioral and psychiatric symptoms relevant to neurodegenerative disease prevent and/or treat method.
Project 3
As described in project 1, prevent and/or treat method, its be a kind of impulsion symptom relevant to mental sickness prevent and/or treat method.
Project 4
As as described in project 2, prevent and/or treat method, wherein, described neurodegenerative disease is selected from dementia, multiple sclerosis, parkinson's syndrome (Parkinson syndrome), juvenile stage parkinson disease (juvenile parkinsonism), striatonigral degeneration (striatonigral degeneration), Progressive symmetric erythrokeratodermia core benumbs (progressive supranuclearpalsy), motion can not (pure akinesia) completely, prion disease (prion disease), cortical basal ganglionic degeneration (corticobasaldegeneration), chorea acanthocytosis (chorea-acanthocytosis), optimum heritability chorea (benign hereditary chorea), paroxysmal choreoathetosis (paroxysmal choreoathetosis), essential tremor (essential tremor), essential myoclonus (essential myoclonus), gilles de la Tourette syndrome (Gilles de la Tourette syndrome), Rett syndrome (Rett syndrome), degeneration ballism (degenerativeballism), dystonia musculorum deformans (dystonia musculorum deformans), athetosis (athetosis), spasmodic torticollis (spasmodic torticollis), the hot syndrome of prunus mume (sieb.) sieb.et zucc. (Meige syndrome), cerebral palsy (cerebralpalsy), hepatolenticular degeneration (Wilson ' s disease), rapids Chuan Shi disease (Segawa ' s disease), Ha-Shi syndrome (Hallervorden-Spatz syndrome), neural axon malnutrition (neuroaxonal dystrophy), pallidal atrophy (pallidal atrophy), spinocerebellar degeneration (spinocerebellar degeneration), cerebral cortical atrophy (cerebral cortical atrophy), Holmes type cerebellar atrophy (Holmes-type cerebellar atrophy), olivopontocerebellar atrophy (olivopontocerebellar atrophy), heritability olivopontocerebellar atrophy (hereditaryolivopontocerebellar atrophy), Joseph disease (Joseph disease), dentatorubropallidoluysian atrophy (dentatorubropallidoluysian atrophy), Ge-Shi-Sha syndrome (Gerstmann-Straussler-Scheinkersyndrome), Friedreich ataxia (Friedreich ataxia), Lu-Lai syndrome (Roussy-Levysyndrome), Mei-Huai syndrome (May-White syndrome), congenital cerebellar ataxia (congenital cerebellarataxia), periodically hereditary ataxia (periodic hereditary ataxia), Ataxia telangiectasia (ataxia telangiectasia), amyotrophic lateral sclerosis (amyotrophic lateral sclerosis), progressive bulbar palsy (progressive bulbar palsy), myelopathic muscular atrophy (spinal progressive muscular atrophy), spinobulbar muscular atrophy (spinobulbar muscular atrophy), Wei-Huo disease (Werdnig-Hoffmann disease), Ku-Wei disease (Kugelberg-Welander disease), hereditary spastic paraplegia (hereditary spastic paraplegia), syringomyelia (syringomyelia), syringobulbia (syringobulbia), A-Xi deformity (Arnold-Chiarimalformation), stiff man syndrome (stiff man syndrome), Ke-Fei syndrome (Klippel-Feil syndrome), Fazio-Londe disease (Fazio-Londe disease), low myelopathy (low myelopathy), Dan-Wo syndrome (Dandy-Walkersyndrome), spina bifida (spina bifida), She-La syndrome (Sjogren-Larsson syndrome), radiation myelopathy (radiation myelopathy), age-related macular degeneration, and the apoplexy to cause due to cerebral hemorrhage and/or relative dysfunction or neurological deficit.
Project 5
As described in project 4, prevent and/or treat method, wherein, described neurodegenerative disease is dull-witted.
Project 6
As described in project 5, prevent and/or treat method, wherein, described dementia is dementia of the Alzheimer type.
Project 7
As described in project 5, prevent and/or treat method, wherein, described dementia is dementia with Lewy body.
Project 8
As described in project 5, prevent and/or treat method, wherein, described dementia is Frontotemporal dementia.
Project 9
As described in project 5, prevent and/or treat method, wherein, described dementia is vascular dementia.
Project 10
As described in project 5, prevent and/or treat method, wherein, described dementia is that Parkinson is dull-witted.
Project 11
As described in project 5, prevent and/or treat method, wherein, described dementia is Huntington Chorea.
Project 12
As described in project 4, prevent and/or treat method, wherein, described neurodegenerative disease is multiple sclerosis.
Project 13
As as described in project 3, prevent and/or treat method, wherein, described mental sickness is selected from schizophrenia, refractory schizophrenia (treatment-resistant schizophrenia), refractory schizophrenics refractoryschizophrenia), chronic schizophrenia (chronic schizophrenia), dysthymic disorder (emotional disturbance), mental disorder (psychotic disorder), mood disorders (mood disorder), bipolar disorder (bipolar disorder), mania (mania), depression (depression), endogenous depression (endogenous depression), major depression (major depression), melancholic and refractory depression (melancholic and treatment-resistantdepression), dysthymic disorder (dysthymic disorder), circular type's affective disorder (cyclothymic disorder), anxiety disorder (anxiety disorder), somatic disturbance (somatoform disorder), do factitious disorder (factitiousdisorder), dissociative disorder (dissociative disorder), sexual disorders (sexual disorder), eating disorders (eatingdisorder), sleep disorder (sleep disorder), adjustment disorder (adjustment disorder), Substance-related disorders (substance-related disorder), anhedonia (anhedonia), delirium (delirium), vomiting (vomiting), motion sickness (motion sickness), obesity (obesity), migraine (migraine), pain (pain), mental retardation (mental retardation), autism (autism), tourette's disorder (Tourette ' s disorder), Tic disorders (tic disorder), attention deficit hyperactivity disorder (attention deficit hyperactivity disorder), conduct disorder (conduct disorder), intermittent explosive disorder (intermittent explosive disorder), kleptomania (kleptomania), pyromania (pyromania), Pathological Gambling (pathological gambling), trichotillomania (trichotillomania), mongolism (Down ' s syndrome) and personality disorder (personality disorder).
Project 14
As described in project 13, prevent and/or treat method, wherein, described mental sickness is selected from schizophrenia, refractory schizophrenia, refractory schizophrenics and chronic schizophrenia.
Project 15
As described in project 13, prevent and/or treat method, wherein, described mental sickness is selected from depression, endogenous depression, major depression, melancholic and refractory depression.
Project 16
As described in project 13, prevent and/or treat method, wherein, described mental sickness is bipolar disorder.
Project 17
As described in project 13, prevent and/or treat method, wherein, described mental sickness is eating disorders.
Project 18
As described in project 13, prevent and/or treat method, wherein, described mental sickness is attention deficit hyperactivity disorder.
Project 19
As described in project 13, prevent and/or treat method, wherein, described mental sickness is anxiety disorder.
Project 20
As described in project 19, prevent and/or treat method, wherein, described anxiety disorder is obsession (obsessive-compulsive disorder).
Project 21
As described in project 19, prevent and/or treat method, wherein, described anxiety disorder is posttraumatic stress disorder (post-traumatic stress disorder).
Project 22
As prevented and/or treated method in project 1 to 21 as described in any one, wherein, patient can not obtain for the behavioral and psychiatric symptoms relevant to neurodegenerative disease or the effect of impulsion symptom abundance of being correlated with mental sickness from the medicine of usually available antipsychotic drug or neurodegenerative disease.
Project 23
As as described in project 22, prevent and/or treat method, wherein, described usually available antipsychotic drug is chlorpromazine (chlorpromazine), fluphenazine (fluphenazine), levomepromazine (levomepromazine), perphenazine (perphenazine), periciazine (propericiazine), bromperidol (bromperidol), haloperidol (haloperidol), pipamperone (pipamperone), timiperone (timiperone), nemonapride (nemonapride), sulpiride (sulpiride), sultopride (sultopride), carpipramine (carpipramine), clocapramine (clocapramine), mosapramine (mosapramine), pimozide (pimozide), oxypertine (oxypertine), zotepine (zotepine), amisulpride (amisulpride), risperidone (risperidone), iloperidone (iloperidone), cis-N-[4-[4-(1,2-Benzisothiazol-3-yl)-1-piperazinyl (perospirone), 9-hydroxy-risperidone (paliperidone), Lurasidone (lurasidone), Ziprasidone (ziprasidone), asenapine (asenapine), clozapine (clozapine), olanzapine (olanzapine), Quetiapine (quetiapine), blonanserin (blonanserin), Aripiprazole (aripiprazole), the vertical piperazine (cariprazine) of card or Sertindole (sertindole), or their salt.
Project 24
Method is prevented and/or treated as described in project 22, wherein, the medicine of described usually available neurodegenerative disease is donepezil (donepezil), galantamine (galantamine), Rivastigmine (rivastigmine), memantine (memantine), FTY720 (fingolimod), methylprednisolone (methylprednisolone), azathioprine (azathioprine), mitoxantrone (mitoxantrone), cyclophosphamide (cyclophosphamide), interferon-β preparation (interferon β preparation), Ge La is for thunder (glatiramer), teriflunomide (teriflunomide) or natalizumab (natalizumab), or their salt.
Project 25
Prevent and/or treat an agent for the behavioral and psychiatric symptoms relevant to neurodegenerative disease or the impulsion symptom of being correlated with mental sickness, it contains 7-[4-(4-benzo [b] thiophene-4-base-piperazine-1-base) butoxy]-1H-quinoline-2-one-or its salt as effective ingredient.
Project 26
As described in project 25, prevent and/or treat agent, it is prevent and/or treat agent for the behavioral and psychiatric symptoms relevant to neurodegenerative disease.
Project 27
As described in project 25, prevent and/or treat agent, it is prevent and/or treat agent for the impulsion symptom relevant to mental sickness.
Project 28
As as described in project 26, prevent and/or treat agent, wherein, described neurodegenerative disease is selected from dementia, multiple sclerosis, parkinson's syndrome, juvenile stage parkinson disease, striatonigral degeneration, Progressive symmetric erythrokeratodermia core is benumbed, motion can not completely, prion disease, cortical basal ganglionic degeneration, chorea acanthocytosis, optimum heritability chorea, paroxysmal choreoathetosis, essential tremor, essential myoclonus, gilles de la Tourette syndrome, Rett syndrome, degeneration ballism, dystonia musculorum deformans, athetosis, spasmodic torticollis, the hot syndrome of prunus mume (sieb.) sieb.et zucc., cerebral palsy, hepatolenticular degeneration, rapids Chuan Shi is sick, Ha-Shi syndrome, neural axon malnutrition, pallidal atrophy, spinocerebellar degeneration, cerebral cortical atrophy, Holmes type cerebellar atrophy, olivopontocerebellar atrophy, heritability olivopontocerebellar atrophy, Joseph disease, dentatorubropallidoluysian atrophy, Ge-Shi-Sha syndrome, Friedreich ataxia, Lu-Lai syndrome, Mei-Huai syndrome, congenital cerebellar ataxia, periodically hereditary ataxia, Ataxia telangiectasia, amyotrophic lateral sclerosis, progressive bulbar palsy, myelopathic muscular atrophy, spinobulbar muscular atrophy, Wei-Huo is sick, Ku-Wei is sick, hereditary spastic paraplegia, syringomyelia, syringobulbia, A-Xi deformity, stiff man syndrome, Ke-Fei syndrome, Fazio-Londe disease, low myelopathy, Dan-Wo syndrome, spina bifida, She-La syndrome, radiation myelopathy, age-related macular degeneration, and the apoplexy to cause due to cerebral hemorrhage and/or relative dysfunction or neurological deficit.
Project 29
As described in project 28, prevent and/or treat agent, wherein, described neurodegenerative disease is dull-witted.
Project 30
As described in project 29, prevent and/or treat agent, wherein, described dementia is dementia of the Alzheimer type.
Project 31
As described in project 29, prevent and/or treat agent, wherein, described dementia is dementia with Lewy body.
Project 32
As described in project 29, prevent and/or treat agent, wherein, described dementia is Frontotemporal dementia.
Project 33
As described in project 29, prevent and/or treat agent, wherein, described dementia is vascular dementia.
Project 34
As described in project 29, prevent and/or treat agent, wherein, described dementia is that Parkinson is dull-witted.
Project 35
As described in project 29, prevent and/or treat agent, wherein, described dementia is Huntington Chorea.
Project 36
As described in project 28, prevent and/or treat agent, wherein, described neurodegenerative disease is multiple sclerosis.
Project 37
Agent is prevented and/or treated as described in project 27, wherein, described mental sickness is selected from schizophrenia, refractory schizophrenia, refractory schizophrenics, chronic schizophrenia, dysthymic disorder, mental disorder, mood disorders, bipolar disorder, mania, depression, endogenous depression, major depression, melancholic and refractory depression, dysthymic disorder, circular type's affective disorder, anxiety disorder, somatic disturbance, do factitious disorder, dissociative disorder, sexual disorders, eating disorders, sleep disorder, adjustment disorder, Substance-related disorders, anhedonia, delirium, vomiting, motion sickness, obesity, migraine, pain, mental retardation, autism, tourette's disorder, Tic disorders, attention deficit hyperactivity disorder, conduct disorder, intermittent explosive disorder, kleptomania, pyromania, Pathological Gambling, trichotillomania, mongolism and personality disorder.
Project 38
As described in project 37, prevent and/or treat agent, wherein, described mental sickness is selected from schizophrenia, refractory schizophrenia, refractory schizophrenics and chronic schizophrenia.
Project 39
As described in project 37, prevent and/or treat agent, wherein, described mental sickness is selected from depression, endogenous depression, major depression, melancholic and refractory depression.
Project 40
As described in project 37, prevent and/or treat agent, wherein, described mental sickness is bipolar disorder.
Project 41
As described in project 37, prevent and/or treat agent, wherein, described mental sickness is eating disorders.
Project 42
As described in project 37, prevent and/or treat agent, wherein, described mental sickness is attention deficit hyperactivity disorder.
Project 43
As described in project 37, prevent and/or treat agent, wherein, described mental sickness is anxiety disorder.
Project 44
As described in project 43, prevent and/or treat agent, wherein, described anxiety disorder is obsession.
Project 45
As described in project 43, prevent and/or treat agent, wherein, described anxiety disorder is posttraumatic stress disorder.
Project 46
As prevented and/or treated agent in project 25 to 45 as described in any one, it for not obtaining for the behavioral and psychiatric symptoms relevant to neurodegenerative disease or the treatment of the patient of the effect of impulsion symptom abundance of being correlated with mental sickness from the medicine of usually available antipsychotic drug or neurodegenerative disease.
Project 47
Agent is prevented and/or treated as described in project 46, wherein, described usually available antipsychotic drug is chlorpromazine, fluphenazine, levomepromazine, perphenazine, periciazine, bromperidol, haloperidol, pipamperone, timiperone, nemonapride, sulpiride, sultopride, carpipramine, clocapramine, mosapramine, pimozide, oxypertine, zotepine, amisulpride, risperidone, iloperidone, cis-N-[4-[4-(1,2-Benzisothiazol-3-yl)-1-piperazinyl, 9-hydroxy-risperidone, Lurasidone, Ziprasidone, asenapine, clozapine, olanzapine, Quetiapine, blonanserin, Aripiprazole, the vertical piperazine of card or Sertindole, or their salt.
Project 48
Agent is prevented and/or treated as described in project 46, wherein, the medicine of described usually available neurodegenerative disease is donepezil, galantamine, Rivastigmine, memantine, FTY720, methylprednisolone, azathioprine, mitoxantrone, cyclophosphamide, interferon-β preparation, lattice draw for thunder, teriflunomide or natalizumab, or their salt.
Project 49
7-[4-(4-benzo [b] thiophene-4-base-piperazine-1-base) butoxy]-1H-quinoline-2-one-or its salt are for the production of the behavioral and psychiatric symptoms relevant to neurodegenerative disease or the purposes preventing and/or treating agent of impulsion symptom of being correlated with mental sickness.
Project 50
For the behavioral and psychiatric symptoms relevant to neurodegenerative disease or 7-[4-(4-benzo [b] thiophene-4-base-piperazine-1-base) the butoxy]-1H-quinoline-2-one-prevented and/or treated of impulsion symptom of being correlated with mental sickness or its salt.
Project 51
For the behavioral and psychiatric symptoms relevant to neurodegenerative disease or the pharmaceutical composition prevented and/or treated of impulsion symptom of being correlated with mental sickness, it comprises 7-[4-(4-benzo [b] thiophene-4-base-piperazine-1-base) butoxy]-1H-quinoline-2-one-or its salt as effective ingredient.
Project 52
As described in project 13, prevent and/or treat method, wherein, described mental sickness is Substance-related disorders.
Project 53
As described in project 52, prevent and/or treat method, wherein, described Substance-related disorders is Mental disorders due to alcohol (alcohol-related disorder).
Project 54
As described in project 37, prevent and/or treat agent, wherein, described mental sickness is Substance-related disorders.
Project 55
As described in project 54, prevent and/or treat agent, wherein, described Substance-related disorders is Mental disorders due to alcohol.
Project 56
As described in project 6, prevent and/or treat method, wherein, described behavioral and psychiatric symptoms is impulsion symptom.
Project 57
As described in project 56, prevent and/or treat method, wherein, described impulsion symptom is exciting (agitation).
Project 58
As described in project 30, prevent and/or treat agent, wherein, described behavioral and psychiatric symptoms is impulsion symptom.
Project 59
As described in project 58, prevent and/or treat agent, wherein, described impulsion symptom is exciting.
Beneficial effect
The behavioral and psychiatric symptoms that epirizole is sent or its salt pair is relevant to neurodegenerative disease or the impulsion symptom of being correlated with mental sickness have excellent curative effect.Epirizole group or its salt especially have excellent curative effect to the behavioral and psychiatric symptoms (BPSD) relevant to dull-witted (preferred Alzheimer).These symptoms can also be improved by the antipsychotic drug or medicine additionally using epirizole group or its salt and existing neurodegenerative disease to the patient that can not obtain sufficient effect from existing medicine.In addition, epirizole group or the neurocyte of its salt activator in middle prefrontal cortex.And epirizole group or its salt are better than existing antipsychotic drug in safety and drug resistance, and can use safely to old patients with Alzheimer disease.
Accompanying drawing explanation
Fig. 1 display confirms the result of the aggressive preliminary test of the lifting of Tg2576 mice.
Fig. 2 shows the result of the test of epirizole group to the aggressive inhibition of Tg2576 mice.
Fig. 3 is presented at and limitedly enjoys in pattern (limited access paradigm) impact of using the individual average ethanol of epirizole party and taking in.
Fig. 4 shows the impact of epirizole group on prefrontal cortex neuron activation pattern in c-fos-GFP mice, and wherein compared with vehicle group, the region that GFP signal significantly increases is shown as white.
Detailed description of the invention
Active component in the present invention is epirizole group or its salt.Epirizole group is a kind of known compound be expressed from the next, and is in the clinical trial process of schizophrenia etc.
The salt of epirizole group is not particularly limited, as long as it is pharmacologically acceptable salt, and can mention, such as, slaine, as alkali metal salt (such as, sodium salt, potassium salt etc.), alkali salt (such as, calcium salt, magnesium salt etc.) etc.; Ammonium salt; With the salt of inorganic base, described inorganic base as alkali carbonate (such as, lithium carbonate, potassium carbonate, sodium carbonate, cesium carbonate etc.), alkali metal hydrogencarbonate (such as, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate etc.), alkali metal hydroxide (such as, Lithium hydrate, sodium hydroxide, potassium hydroxide, Cesium hydrate. etc.) etc.; With the salt of organic base, described organic base as three (rudimentary) alkylamine (such as, trimethylamine, triethylamine, N-ethyl diisopropylamine etc.), pyridine, quinoline, piperidines, imidazoles, picoline, dimethyl aminopyridine, dimethylaniline, N-(rudimentary) alkyl-morpholine (such as, N-methylmorpholine etc.), 1,5-diazabicyclo [4.3.0]-5-in ninth of the ten Heavenly Stems alkene (DBN), 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene (DBU), Isosorbide-5-Nitrae-diazabicylo [2.2.2] octane (DABCO) etc.; With the salt of mineral acid, as hydrochloride, hydrobromide, hydriodide, sulfate, nitrate, phosphate etc.; With organic acid salt, as formates, acetate, propionate, oxalates, malonate, succinate, fumarate, maleate, lactate, malate, citrate, tartrate, carbonate, picrate, mesylate, esilate, tosilate, glutamate, Glu etc.; Deng." (rudimentary) alkyl " refers to " having the alkyl of 1 to 6 carbon atom " as used herein.
Described " epirizole group or its salt " comprises anhydride and the solvate (such as, hydrate, preferably dihydrate) of epirizole group or its salt, the various crystal forms of these anhydrides and solvate, and their mixture.
Separately a kind of this epirizole group or its salt can be used, or also can use its two or more mixture.The anhydride of epirizole group or its salt can be obtained by the method described in the embodiment 1 and embodiment 42-47 of such as patent documentation 1 (JP-A-2006-316052 (US 2010/0179322 A1)).
Epirizole group or its salt can in bulkly use, or preferably use with the form with the pharmaceutical preparation of Conventional pharmaceutical carriers (pharmaceutically acceptable carrier) or diluent.Dosage form is not confined to particular form.Especially, it can be arbitrary conventional administration form, and such as, oral dosage form, as tablet, capsule and granule; Be applicable to Orally administered various liquid preparations; Or parenteral administration, as injection and suppository.Dosage is not confined to particular range.Usually, active component can with about 0.01 to 10mg/ day/amount of 1kg body weight uses.Described active component can be comprised with 0.1-400mg about in the preparation of every dosage unit.
Preparation for injecting is prepared into the form of liquid preparation, Emulsion or suspension usually, by their sterilizings and preferably to make further blood be isotonic.The preparation of liquid, Emulsion or form of suspension is usually by using customary pharmaceutical diluents (as prepared by water, ethanol, propylene glycol, ethoxylation isooctadecane alcohol, propoxylation isooctadecane alcohol and polyoxyethylene sorbitan fatty acid ester.These preparations can by mixing prepare with enough isotonic agent (as sodium chloride, glucose, glycerol) for making isotonic amount, and can further by with the solubilizing agent of routine, buffer agent, anesthetis and optionally, prepared by the mixing of coloring agent, antiseptic, aromatic substance, flavoring agent or sweeting agent.
Described preparation (as tablet, capsule, oral liquid) can be prepared by conventional method.Tablet can be prepared by mixing epirizole group or its salt and Conventional pharmaceutical carriers (as gelatin, starch, lactose, magnesium stearate, Talcum, Radix Acaciae senegalis etc.).Capsule can fill hard gelatin capsule with described mixture or prepared by soft capsule by mixing epirizole group or its salt and inert pharmaceutical filler or diluent.Oral liquid formulations (as syrup or elixir) is prepared by mixing epirizole group or its salt and sweeting agent (such as sucrose), antiseptic (such as methyl parahydroxybenzoate, propyl p-hydroxybenzoate), coloring agent, flavoring agent etc.The preparation of parenteral administration also can be prepared by conventional method, such as, is prepared by dissolving epirizole group or its salt in sterile aqueous carrier (preferred water or saline solution).Then the liquid preparation being preferably suitable for parenteral administration is dissolve in the Polyethylene Glycol of 300 to 5000 to prepare at molecular weight by dissolving the epirizole group of about 0.1-400mg or its salt in water and organic solvent further, wherein preferably lubricant can be added, as sodium carboxymethyl cellulose, methylcellulose, polyvinylpyrrolidone and polyvinyl alcohol.Preferably, above liquid preparation can comprise disinfectant (such as benzyl alcohol, phenol, thimerosal), antibacterial further, and further optionally, isotonic agent (such as sucrose, sodium chloride), local anesthetic, stabilizing agent, buffer agent etc.Consider maintenance stability, the preparation of described parenteral administration can be put into small container, then remove aqueous medium by conventional lyophilizing technique.When deployed, described preparation can revert to liquid preparation by dissolving in an aqueous medium.
The present invention is by taking epirizole group or its salt prevents and/or treat the behavioral and psychiatric symptoms relevant to neurodegenerative disease or the impulsion symptom relevant with mental sickness.
The example of mental sickness of the present invention comprises schizophrenia, refractory schizophrenia, refractory schizophrenics, chronic schizophrenia, dysthymic disorder, mental disorder, mood disorders, bipolar disorder (such as, two-phase I type obstacle and two-phase II type obstacle etc.), mania, depression, endogenous depression, major depression, melancholic and refractory depression, dysthymic disorder, circular type's affective disorder, anxiety disorder (such as, panic attack (panic attack), Panic-stricken (panic disorder), agoraphobia (agoraphobia), social phobia (social phobia), obsession, posttraumatic stress disorder, generalized anxiety disorder (generalized anxiety disorder), acute stress disorder (acutestress disorder) etc.), somatic disturbance (such as, hysteria (hysteria), somatization disorder (somatization disorder), conversive disorder (conversion disorder), pain disorder (pain disorder), hypochondria (hypochondria) etc.), do factitious disorder, dissociative disorder, sexual disorders (such as, sexual dysfunction (sexual dysfunction), dysaphrodisia (sexualdesire disorder), property wakes obstacle (sexual arousal disorder) up, erection disturbance (erectile dysfunction), sexual perversion (paraphilias) etc.), eating disorders (such as, nervous anorexia (anorexia nervosa), bulimia nervosa (bulimia nervosa) etc.), sleep disorder, adjustment disorder, Substance-related disorders (such as, Mental disorders due to alcohol (alcohol use disorders (alcohol use disorder), ethanol brings out sexual disorders (alcohol-induced disorder), alcohol abuse (alcohol abuse), alcohol dependence (alcohol dependence), alcoholism (alcohol intoxication), ethanol withdrawal (alcohol withdrawal) etc.), amphetamine related disorders (amphetamine-related disorders) (amphetamine uses obstacle (amphetamine use disorder) etc.), Cannabis-Related obstacle (cannabis-relateddisorders) (Fructus Cannabis uses obstacle (cannabis use disorder) etc.), Cocaine-Related obstacle (cocaine-relateddisorders) (order cocaine use die (cocaine use disorder) etc.), hallucinogen related disorders (hallucinogen-related disorders) (hallucinogen use disorder (hallucinogen use disorder) etc.) etc.), anhedonia (such as, iatrogenic anhedonia (iatrogenic anhedonia), the anhedonia (anhedonia of a psycic or mental cause) that psychology or spirit cause, the anhedonia (anhedonia associated withdepression) that depression is relevant, the anhedonia (anhedonia associated with schizophrenia) etc. that schizophrenia is relevant), delirium, vomiting, motion sickness, obesity, migraine, pain, mental retardation, autism, tourette's disorder, Tic disorders, attention deficit hyperactivity disorder, conduct disorder, mongolism, personality disorder, intermittent explosive disorder, kleptomania, pyromania, Pathological Gambling, trichotillomania etc.
The example of neurodegenerative disease of the present invention comprises dementia (such as, dementia of the Alzheimer type, dementia with Lewy body, Frontotemporal dementia, vascular dementia, Parkinson is dull-witted, Huntington Chorea, senile dementia (senile dementia), mild cognitive impairment (mild cognitive impairment), HIV encephalopathy (HIV encephalopathy), cortical basal ganglionic degeneration, Pick disease (Pick ' s disease), Mixed dementia (mixed dementia) etc.), multiple sclerosis, parkinson's syndrome, juvenile stage parkinson disease, striatonigral degeneration, Progressive symmetric erythrokeratodermia core is benumbed, motion can not completely, prion disease, cortical basal ganglionic degeneration, chorea acanthocytosis, optimum heritability chorea, paroxysmal choreoathetosis, essential tremor, essential myoclonus, gilles de la Tourette syndrome, Rett syndrome, degeneration ballism, dystonia musculorum deformans, athetosis, spasmodic torticollis, the hot syndrome of prunus mume (sieb.) sieb.et zucc., cerebral palsy, hepatolenticular degeneration, rapids Chuan Shi is sick, Ha-Shi syndrome, neural axon malnutrition, pallidal atrophy, spinocerebellar degeneration, cerebral cortical atrophy, Holmes type cerebellar atrophy, olivopontocerebellar atrophy, heritability olivopontocerebellar atrophy, Joseph disease, dentatorubropallidoluysian atrophy, Ge-Shi-Sha syndrome, Friedreich ataxia, Lu-Lai syndrome, Mei-Huai syndrome, congenital cerebellar ataxia, periodically hereditary ataxia, Ataxia telangiectasia, amyotrophic lateral sclerosis, progressive bulbar palsy, myelopathic muscular atrophy, spinobulbar muscular atrophy, Wei-Huo is sick, Ku-Wei is sick, hereditary spastic paraplegia, syringomyelia, syringobulbia, A-Xi deformity, stiff man syndrome, Ke-Fei syndrome, Fazio-Londe disease, low myelopathy, Dan-Wo syndrome, spina bifida, She-La syndrome, radiation myelopathy, age-related macular degeneration, and the apoplexy etc. to cause due to cerebral hemorrhage and/or relevant dysfunction or neurological deficit.
Behavioral and psychiatric symptoms of the present invention is impulsion symptom and mental symptom.
Described impulsion symptom takes the symptom of impulsive behavior.The particular instance of impulsive behavior comprises physical aggression (physicalattack), absentminded (wandering), be on tenterhooks (restlessness), exciting (agitation), unconscious behavior (senseless behavior) and Deviant Behavior (deviant behavior) (such as, paraphilia behavior (sexual deviantbehavior)), roaming (roaming), cacophony (shrill voice), scream (screaming), violence language (violentlanguage), lose power (loss of motivation), constantly question closely (constant questioning), follow the tracks of (shadowing), suicide attempts (suicide attempt) and suicide (suicide), Self-injurious behavior (self-injuriousbehavior), threaten (threat), stealing (stealing), overeating (overeating), coercive act (act ofthreatening), short circuit reaction (short-circuit reaction), panic reaction (panic reaction), property damage (propertydamage), improper wear the clothes/undress (inappropriate dressing/undressing), sell off (underselling) etc.In a preferred embodiment, described impulsion symptom is exciting.
The example of mental symptom comprises hallucination (hallucination), vain hope (delusion), depressed (depressedmood), insomnia, anxiety, wrong identification (misrecognition), sleep disorder (sleep disorder) etc.
In the present invention, the method that prevents and/or treats of behavioral and psychiatric symptoms refers to the method for the patient's condition preventing and/or treat the one or more symptoms occurred in above-mentioned behavioral and psychiatric symptoms.
In the present invention, the method that prevents and/or treats of impulsion symptom refers to the method for the patient's condition preventing and/or treat the one or more symptoms occurred in above-mentioned impulsion symptom.
In the present invention, epirizole group or its salt pair following symptoms prevent and/or treat particularly useful: 1) relevant to neurodegenerative disease behavioral and psychiatric symptoms, wherein, described neurodegenerative disease be dull-witted (BPSD) (further, 1) wherein said neurodegenerative disease is in the behavioral and psychiatric symptoms relevant to neurodegenerative disease of dull-witted (BPSD), particularly useful to preventing and/or treating of following symptoms: the behavioral and psychiatric symptoms relevant to dementia of the Alzheimer type, the behavioral and psychiatric symptoms relevant to dementia with Lewy body, the behavioral and psychiatric symptoms relevant to Frontotemporal dementia, the behavioral and psychiatric symptoms relevant to vascular dementia, the behavioral and psychiatric symptoms dull-witted relevant to Parkinson, the behavioral and psychiatric symptoms relevant to Huntington Chorea), or 2) behavioral and psychiatric symptoms relevant to neurodegenerative disease, wherein, described neurodegenerative disease is multiple sclerosis.
In addition, in the present invention, epirizole group or its salt pair following symptoms prevent and/or treat particularly useful: 1) relevant to mental sickness impulsion symptom, wherein, described mental sickness is selected from schizophrenia, refractory schizophrenia, refractory schizophrenics and chronic schizophrenia; 2) relevant to mental sickness impulsion symptom, wherein, described mental sickness is selected from depression, endogenous depression, major depression, melancholic and refractory depression; 3) relevant to mental sickness impulsion symptom (wherein, described mental sickness is bipolar disorder), 4) relevant to mental sickness impulsion symptom, wherein, described mental sickness is eating disorders; 5) relevant to mental sickness impulsion symptom, wherein, described mental sickness is attention deficit hyperactivity disorder; Or 6) relevant to mental sickness impulsion symptom, wherein said mental sickness be anxiety disorder (further, described mental sickness is 6 of anxiety disorder wherein) in the impulsion symptom relevant to mental sickness, useful to preventing and/or treating of the impulsion symptom relevant to obsession or posttraumatic stress disorder).
Even if in the patient of medicine taking one or more antipsychotic drug and spiritual degenerative disease, above-mentioned symptom also can not improve sometimes.Described symptom can by use to such patient epirizole group or its salt improve.
The example of the antipsychotic drug of existing (usually available) comprises chlorpromazine, fluphenazine, levomepromazine, perphenazine, periciazine, bromperidol, haloperidol, pipamperone, timiperone, nemonapride, sulpiride, sultopride, carpipramine, clocapramine, mosapramine, pimozide, oxypertine, zotepine, amisulpride, risperidone, iloperidone, cis-N-[4-[4-(1,2-Benzisothiazol-3-yl)-1-piperazinyl, 9-hydroxy-risperidone, Lurasidone, Ziprasidone, asenapine, clozapine, olanzapine, Quetiapine, blonanserin, Aripiprazole, the vertical piperazine of card, Sertindole, or their salt etc.
The example of the medicine of the neurodegenerative disease of existing (usually available) comprises Aricept (registered trade mark) (donepezil hydrochloride), Reminyl (registered trade mark) (galanthamine hydrobromide), Exelon (registered trade mark) plaster (absorption preparation of Rivastigmine percutaneous dosing), Rivastach (registered trade mark) plaster (absorption preparation of Rivastigmine percutaneous dosing), Memary (registered trade mark) (memantine), fingolimod hydrochloride (fingolimod hydrochloride) (Gilenya (registered trade mark) capsule, Imusera (registered trade mark) capsule), methylprednisolone, azathioprine, mitoxantrone, cyclophosphamide, interferon-β preparation, Copaxone (registered trade mark) (acetic acid copaxone), teriflunomide, Tysabri (registered trade mark) (natalizumab) etc.
Embodiment
Embodiment 1
1) measurement of mice circadian rhythm motor behavior
Animal: breed the APPSL-Tg mice (male) having Sweden and London APP and suddenly change, and the non-Tg mice (male) without gene mutation in contrast, raise in receptacle, and they become 6 months large after use.In feeding process, isolation is used to live.
Measuring method: use the SUPERMEX manufactured by Shi Ding Machinery Co., Ltd. (Muromachi Kikai Co., Ltd.) to carry out the measurement of circadian rhythm motor behavior.Mice is put into independent cage, and under the condition of free feeding, drinking-water, measures the autonomic movement behavior 3 days (amounting to 62.5hr) of mice.In the instrument, passive infrared sensor detects the infrared light sent from described mice, and the quantity of counting transposition.Every 30min adds up to the value measured, and uses special software CompACT AMS automatically to add up to.Described test is carried out in soundproof room, so that the autonomic movement behavior of mice is unaffected.Lighting hours in soundproof room is set to 7:00-19:00 as in receptacle.
2) divided into groups by preliminary test
Measure the amount of the autonomic movement behavior of non-Tg mice and APPSL-Tg mice during the dark period of 19:00-7:00 in advance.Mice divides into groups in the following way: use body weight and dark period autonomic movement behavior as index, make the meansigma methods of described group equal with variance.
3) preparation of medicine and application process
Epirizole group is dissolved in the distilled water containing 5% Radix Acaciae senegalis, vehicle group is used to the distilled water of 5% Radix Acaciae senegalis, and they are used every Mouse oral.
4) quantity of mice and dosage are arranged
Organize 1:5 non-Tg mice/excipient
Organize 2:5 APPSL-Tg mice/excipient
Organize 3:6 APPSL-Tg mice/0.01mg/kg epirizole group
Organize 4:5 APPSL-Tg mice/0.03mg/kg epirizole group
5) time of application
Epirizole group and excipient 3 days is used in the period of 17:30-18:30.After application, start rapidly or proceed the measurement of amount of motor behavior.
6) statistical analysis
Statistics test is two-sided test, and the significance level of test is set to 5%.Use SAS (R9.1, SASInstitute Japan Ltd.) as statistics software.
I) the comparing of non-Tg mice/vehicle group and APPSL-Tg mice/vehicle group
Mixed model is used to carry out repeated measure ANOVA to the 1st-3 evening in evening at each stage I, II or III of dark period.In addition, unpaired t-test is carried out to each dark period and night.
Ii) APPSL-Tg mice/vehicle group is sent with APPSL-Tg mice/epirizole and is used comparing of group
Deng Naite (Dunnett) inspection is carried out based on to using mixed model to carry out repeated measure ANOVA at each stage I, II or III of dark period the 1st-3 evening in evening.In addition, dunnett's test is carried out to each dark period and night
7) result
Experimental result shows in table 1 and table 2.
[table 1]
Non-Tg mice/vehicle group compares with APPSL-Tg mice/vehicle group
Mean+/-standard error
The display of P value uses the result of mixed model repeated measure ANOVA.In addition, by unpaired t-test in each dark period to all analyzing at night.(* P<0.05; * P<0.01vs non-Tg mice/vehicle group).
[table 2]
APPSL-Tg mice/vehicle group is sent with APPSL-Tg mice/epirizole and is used comparing of group
Mean+/-standard error
The display of P value is based on the result of the dunnett's test of the repeated measure ANOVA of use mixed model.In addition, by dunnett's test to analyzing at night.(* * P<0.01, #P=0.068vs APPSL-Tg mice/vehicle group).
Before this, the people such as Vloeberghs have reported, about the autonomic movement behavior of APP-Tg mouse model in 12hr/12hr day-night cycle, along with the age increases, dark period autonomic movement behavior increases (Eur J Neurosci.2004; 10:2757-66).Compared with non-Tg mice group, the APPSL-Tg mice used in the present invention also shows autonomic movement behavior (the II stage: P<0.05 significantly increased in II stage and III stage; The III stage: P<0.01).In addition, for at night in each dark period, described autonomic movement behavior is in the 3rd dark in evening II stage period (P<0.05) or significantly increase (table 1) the late III stage (P<0.01) of the 1st-3 in evening.
Before the dark period, (17:30-18:30) uses epirizole group with the dosage of 0.01 and 0.03mg/kg to APPSL-Tg mice, and starts to measure autonomic movement behavior.Use epirizole group the 2nd day and the 3rd day at same time, and continue to measure autonomic movement behavior.As a result, compared with vehicle group, 0.01mg/kg group and 0.03mg/kg group significantly suppress autonomic movement behavior (0.01mg/kg group: P<0.05 in dark III stage period; 0.03mg/kg group: P=0.050).In addition, at night in dark III stage period, 0.01mg/kg epirizole group significantly suppresses autonomic movement behavior (P<0.01, table 2) in the 3rd evening.And 0.03mg/kg epirizole group also trended towards suppressing (P=0.068, table 2) in the 3rd evening.On the other hand, in non-Tg mice, epirizole group does not reduce autonomic movement behavior in the dark period.
The above results is illustrated, even if when low dosage, epirizole group can suppress to have the Deviant Behavior of AD model mice at night of app gene sudden change.
Embodiment 2
1) settler-invader's test (Resident-Intruder test) (research of impulsion symptom)
Animal: there is Sweden APP sudden change (K670N, M671L) Tg2576 mice (male) and the non-Tg mice (male) without homologous genes sudden change are in contrast bought purchased from Taconic, and raise and grow to 5-6 month greatly.Between feeding period, isolation is used to live.
Measuring method: for this experiment, uses Tg2576 or non-Tg mice [settler] and almost without the A/J mice [invader] of aggressive behavior.Settler forms sufficient manor in 14 days by isolation inhabitation.After this, invader is moved into the cage of settler, and observe aggressive behavior 10min.As aggressive behavior, record is nibbled, and measures the sum nibbled of time and the 10min nibbling for the first time and need.When the amount of the motor behavior of mice is the highest, carry out described measurement dark stage period the 1st (4hr).
2) confirm to attack by preliminary test
Tg2576 (48 mices) and non-Tg mice (10 mices) are carried out in advance settler-invader's test, and confirm the increase of the aggressive behavior of Tg2576 mice.Get rid of five Tg2576 mices without aggressive behavior, then have 43 mices for this test.
3) grouping of Tg2576 mice and dosage are arranged
Mice is divided into 3 groups in the following way: the sum nibbled being used in the time and 10min that first time of obtaining in preliminary test attacks needs as index, with the meansigma methods and variance that make described group equal (amounting to 43 mices).
Organize 1:15 Tg2576 mice/excipient
Organize 2:14 Tg2576 mice/0.01mg/kg epirizole to send (OPC-34712)
Organize 3:14 Tg2576 mice/0.03mg/kg epirizole to send (OPC-34712)
4) preparation of medicine and application process
Epirizole group is dissolved in the distilled water containing 5% Radix Acaciae senegalis, vehicle group is used to the distilled water of 5% Radix Acaciae senegalis, and they are used every Mouse oral.
5) time of application
Before on-test, 1hr uses epirizole group and excipient.
6) statistical analysis
The significance level of test is set to 5%.Use SAS (R9.1, SAS Institute Japan Ltd.) as statistics software.In order to confirm the promotion of the aggressive behavior of Tg2576 mice, analyzed by Wilcoxon rank test compared with non-Tg mice.Using as being sent by epirizole the attack inhibition caused, using following combination to carry out Shirley-Williams multiple comparative test to analyze.
I) Tg2576 mice/vehicle group and Tg2576 mice/0.01mg/kg epirizole group use group
Ii) Tg2576 mice/vehicle group and Tg2576 mice/0.03mg/kg epirizole group use group
7) result
Described assay shows in fig. 1 and 2.
Before this, about the attack of Tg2576 mice, increase (the Behavioural Brain Research 2011 of the people such as Alexander by using settler-invader's test report to attack; 216:77 – 83).The Tg2576 mice used in the present invention is also tested by settler-invader and assesses.As a result, compare with non-Tg mice group, the time that first time nibbles to be needed significantly shortens (Fig. 1 a, P<0.05, Wilcoxon rank test).In addition, the sum nibbled of 10min is also analyzed.As a result, Tg2576 mice demonstrates remarkable increase (Fig. 1 b, P<0.01, Wilcoxon rank test) at the quantitative aspects nibbled.By this way, the identical Tg2576 mice demonstrating the aggressive behavior obviously increased is used to continue the attack inhibition of research epirizole group.
Before starting settler-invader's test, 1hr uses epirizole group with the dosage of 0.01 and 0.03mg/kg to Tg2576 mice, and studies the attack inhibition of epirizole group.Based on the result measured, analyze first time and nibble the time needed.As a result, compare with vehicle group, in 0.03mg/kg group first time nibble need time significant prolongation (Fig. 2 a, vehicle group vs 0.03mg/kg group: *p<0.05, Shirley-Williams multiple comparative test).The quantity of nibbling also is analyzed by identical test.As a result, compared with vehicle group, the Tg2576 mice of using 0.03mg/kg epirizole group trends towards demonstrating the quantity of nibbling (Fig. 2 b, vehicle group vs0.03mg/kg group: P=0.0709) of reduction.
The above results is illustrated, and in the aggressive behavior of AD model mice with app gene sudden change, epirizole group can suppress to attack.
Embodiment 3
By using the novel transgene mouse model of expressing mutant P123H β-synapse nucleoprotein, by the settler-invader's test in the measurement of circadian rhythm motor behavior carried out in embodiment 1 and embodiment 2, and conventional behavior evaluation research (elevated plus-maze test (elevated plus maze test), forced swim test (forced swimmingtest), tail-suspention test (tail suspension test), light/dark case experiment (light/dark box test), bury pearl behavioral experiment (marble burying behavior test), steep cliff avoidance reaction (cliff avoidance response test)) suppression of epirizole group to behavioral and psychiatric symptoms can be assessed.
Embodiment 4
Record has the impulsion symptom of the mice of Disc1 L100P site mutation, can assess epirizole party to get excited the suppression of symptom by the settler-invader's test in the measurement of circadian rhythm motor behavior carried out in embodiment 1 and embodiment 2 and the research of conventional behavior evaluation (elevated plus-maze test, forced swim test, tail-suspention test, the experiment of light/dark case, bury pearl behavioral experiment, steep cliff avoidance reaction).
Embodiment 5
Use in the treatment of experimenter suffering from the excitement relevant to dementia of the Alzheimer type multicenter, random, double blinding, placebo-contrast research to check epirizole is sent (OPC-34712) curative effect, safety and toleration.
Experimental technique
Register according to American National neuropathy and communication obstacle and apoplexy institute and Alzheimer and relevant disease association (National Institute of Neurological and Communicative Disorders and Stroke and theAlzheimer ' s Disease and Related Disorders Association, NINCDS-ADRDA) diagnosis of Alzheimer disease standard diagnostics be suffer from Alzheimer have 5 to 22 mini-mentalstate examination (Mini Mental StateExamination, MMSE) score and at psychoneural scale nursing home edition (Neuropsychiatric Inventory inNursing Home Version, NPI-NH) excitement/attack project has the >=patient of 55 to 90 years old of the score of 4.This test was made up of the double-blind treatment period continuing 12 weeks.Experimenter is assigned to one of them of following group.
● placebo
● epirizole sends 0.5mg (progressively increasing dosage to 0.5mg/ day from 0.25mg/ day)
● epirizole sends 1mg (progressively increasing dosage to 1mg/ day from 0.25mg/ day)
● epirizole sends 2mg (progressively increasing dosage to 2mg/ day from 0.25mg/ day)
Appraisal procedure
Terminal sends the improvement of group to placebo group between with dementia of the Alzheimer type relevant excitement to assess effect, safety and the toleration of epirizole group from recruiting patients to last day of experimental session (12 weeks) at epirizole by comparing.
In order to assess effect, use challenges questionnaire (Cohen-Mansfield Agitation Inventory, CMAI) change in, clinical global impression scale-order of severity (Clinical Global Impression of Severity, CGI-S) score, CMAI subscale score, NPI-NH score (amounts to, psychosis subscale or end item), clinical global impression scale-improvement degree (Clinical Global Impression-Improvement, CGI-I) score and clinical global impression scale-therapeutic index (Clinical Global Impression-Efficacy, CGI-E) score.
The suppression of epirizole group to the behavioral and psychiatric symptoms that Ahl tribulus sea silent sickness is correlated with can be assessed by carrying out said method, and the safety of epirizole group and toleration.
Embodiment 6
1) Ethanol intake is measured by limited pattern of enjoying
Measuring method: by reference to the method (Alcohol 1992 of the people such as Sinclair; 9:441 – 44 and Alcohol & Alcoholism 2001; 36:2-10) the following impulsive behavior assessed ethanol and crave for.First, Wistar rat (male) is allowed freely to take in 10% ethanol water and tap water several weeks when isolating and living.The ethanol of each animal take in stable after, what start only to allow the ethanol of 1hr to take in every day limitedly enjoys pattern, and measures the ethanol absorption of 1hr every day.From being close to limited enjoy pattern before and limited enjoy Pattern completion after immediately measure be filled with in the result of the weight of the water supply bottle of 10% ethanol water calculate ethanol take in.Before using immediately assessing drug actions, 4 days limited is enjoyed in pattern showing and is converted with 100% ethanol the animal taken in more than the average ethanol of 0.4g/kg/hr.This limited model test of enjoying carries out between 9:00AM-12:00PM.
2) preparation of medicine and application process
Epirizole group is dissolved in the distilled water containing 5% Radix Acaciae senegalis.Beginning limited enjoy pattern before 1hr once a day give each Oral Administration in Rats use described medicine 4 days.
3) quantity of animal and dosage are arranged
Use five rats.The epirizole selected sends dosage to be the 0.1mg/kg of the autonomic movement behavior (data do not show) that can not affect Wistar rat under new environment.
4) statistical analysis
The significance level of test is set to 5%.Use SAS (R9.3, SAS Institute Japan Ltd.) as statistics software.To take in and limited average ethanol of enjoying in pattern at 4 days after medicament administration is taken in the limited average ethanol of enjoying in pattern of 4 days before analyzing immediately assessing drug actions by two tail pairing t-inspection (2-tailed paired t-test).
5) result
Described assay shows in figure 3.
Enjoy display in pattern to first 4 days of immediately assessing drug actions limited before one hour, to use epirizole with the dosage of 0.1mg/kg more than the rat that the average ethanol of 0.4g/kg/hr is taken in and send 4 days, and calculate in limited average ethanol absorption of enjoying in pattern.Result confirms, the display of epirizole group statistically limits ethanol significantly and takes in.When observing respectively, the reduction that all rat display ethanol is taken in.
The above results is illustrated, and for 10% ethanol water, epirizole group can suppress the impulsion ethanol of Wistar rat to take in behavior with low dosage limited enjoying in pattern.Because reported nalmefene (confirm to suppress the impulsion drinking behavior of alcohol dependence patient clinically, and can Ethanol intake be controlled) display effect (Alcohol & Alcoholism 2001 in this evaluating system; 36:2-10), so epirizole group also suppresses the impulsion drinking behavior of alcohol dependence patient.
Embodiment 7
1) measurement of the neuron activation pattern of c-fos-GFP (cellular oncogene FBJ osteosarcoma green fluorescent protein (Cellar oncogene FBJosteosarcoma green fluorescent protein)) mice
Measuring method: c-fos is the indirect labelling of neuron viability, and it is expressed when neurocyte activates.The transgenic mice (c-fos-GFP mice) of green fluorescent protein (GFP) gene is introduced in the promoter downstream being used in c-fos gene, measures the neuron activation pattern in brain.Use epirizole group or excipient, and be separated brain after 3hr.Two Photon Fluorescence is used to store the GFP signal of the serial section from whole brain in a computer, and, after three-dimensional reconstruction, use brain atlas information quantitative analysis epirizole to send the neuron activation pattern of (OPC-34712) and vehicle group.
2) preparation of medicine and application process
Use to c-fos-GFP Mouse oral in the distilled water that epirizole group is suspended in containing 5% Radix Acaciae senegalis.
3) quantity of mice and dosage are arranged
Use five to seven mices.The dosage of epirizole group is 0.3 and 1mg/kg.
4) statistical analysis
The significance level of test is set to 5%.In each brain region between each group relatively in, carry out Tukey multiple comparative test.
5) result
Assay shows in the diagram.Compared with vehicle group, the region that GFP signal significantly strengthens is shown as white.
0.3 and 1mg/kg, epirizole group significantly increases GFP signal in prefrontal cortex (ACA: front cingulate area, PL: proparea, edge, IL: edge inferior segment).
The above results confirms, epirizole group activates the neurocyte in middle prefrontal cortex.
Industrial usability
Epirizole group or its salt are useful as the behavioral and psychiatric symptoms relevant to neurodegenerative disease or the agent that prevents and/or treats of impulsion symptom of being correlated with mental sickness.
The application is based on the 61/718th, No. 305 and the 61/782nd, and No. 467 U.S. Provisional Patent Application, its content is all incorporated to herein by reference.

Claims (51)

1. the behavioral and psychiatric symptoms relevant to neurodegenerative disease or the impulsion symptom of being correlated with mental sickness prevent and/or treat a method, its patient comprising the impulsion symptom preventing and/or treating the behavioral and psychiatric symptoms relevant to neurodegenerative disease to needs or be correlated with mental sickness uses 7-[4-(4-benzo [b] thiophene-4-base-piperazine-1-base) the butoxy]-1H-quinoline-2-one-or its salt that prevent or treat effective dose.
2. according to claim 1ly prevent and/or treat method, its be a kind of behavioral and psychiatric symptoms relevant to neurodegenerative disease prevent and/or treat method.
3. according to claim 1ly prevent and/or treat method, its be a kind of impulsion symptom relevant to mental sickness prevent and/or treat method.
4. according to claim 2ly prevent and/or treat method, wherein, described neurodegenerative disease is selected from dementia, multiple sclerosis, parkinson's syndrome, juvenile stage parkinson disease, striatonigral degeneration, Progressive symmetric erythrokeratodermia core is benumbed, motion can not completely, prion disease, cortical basal ganglionic degeneration, chorea acanthocytosis, optimum heritability chorea, paroxysmal choreoathetosis, essential tremor, essential myoclonus, gilles de la Tourette syndrome, Rett syndrome, degeneration ballism, dystonia musculorum deformans, athetosis, spasmodic torticollis, the hot syndrome of prunus mume (sieb.) sieb.et zucc., cerebral palsy, hepatolenticular degeneration, rapids Chuan Shi is sick, Ha-Shi syndrome, neural axon malnutrition, pallidal atrophy, spinocerebellar degeneration, cerebral cortical atrophy, Holmes type cerebellar atrophy, olivopontocerebellar atrophy, heritability olivopontocerebellar atrophy, Joseph disease, dentatorubropallidoluysian atrophy, Ge-Shi-Sha syndrome, Friedreich ataxia, Lu-Lai syndrome, Mei-Huai syndrome, congenital cerebellar ataxia, periodically hereditary ataxia, Ataxia telangiectasia, amyotrophic lateral sclerosis, progressive bulbar palsy, myelopathic muscular atrophy, spinobulbar muscular atrophy, Wei-Huo is sick, Ku-Wei is sick, hereditary spastic paraplegia, syringomyelia, syringobulbia, A-Xi deformity, stiff man syndrome, Ke-Fei syndrome, Fazio-Londe disease, low myelopathy, Dan-Wo syndrome, spina bifida, She-La syndrome, radiation myelopathy, age-related macular degeneration, and the apoplexy to cause due to cerebral hemorrhage and/or relative dysfunction or neurological deficit.
5. according to claim 4ly prevent and/or treat method, wherein, described neurodegenerative disease is dull-witted.
6. according to claim 5ly prevent and/or treat method, wherein, described dementia is dementia of the Alzheimer type.
7. according to claim 5ly prevent and/or treat method, wherein, described dementia is dementia with Lewy body.
8. according to claim 5ly prevent and/or treat method, wherein, described dementia is Frontotemporal dementia.
9. according to claim 5ly prevent and/or treat method, wherein, described dementia is vascular dementia.
10. according to claim 5ly prevent and/or treat method, wherein, described dementia is that Parkinson is dull-witted.
11. according to claim 5ly prevent and/or treat method, and wherein, described dementia is Huntington Chorea.
12. according to claim 4ly prevent and/or treat method, and wherein, described neurodegenerative disease is multiple sclerosis.
13. according to claim 3ly prevent and/or treat method, wherein, described mental sickness is selected from schizophrenia, refractory schizophrenia, refractory schizophrenics, chronic schizophrenia, dysthymic disorder, mental disorder, mood disorders, bipolar disorder, mania, depression, endogenous depression, major depression, melancholic and refractory depression, dysthymic disorder, circular type's affective disorder, anxiety disorder, somatic disturbance, do factitious disorder, dissociative disorder, sexual disorders, eating disorders, sleep disorder, adjustment disorder, Substance-related disorders, anhedonia, delirium, vomiting, motion sickness, obesity, migraine, pain, mental retardation, autism, tourette's disorder, Tic disorders, attention deficit hyperactivity disorder, conduct disorder, intermittent explosive disorder, kleptomania, pyromania, Pathological Gambling, trichotillomania, mongolism and personality disorder.
14. according to claim 13ly prevent and/or treat method, and wherein, described mental sickness is selected from schizophrenia, refractory schizophrenia, refractory schizophrenics and chronic schizophrenia.
15. according to claim 13ly prevent and/or treat method, and wherein, described mental sickness is selected from depression, endogenous depression, major depression, melancholic and refractory depression.
16. according to claim 13ly prevent and/or treat method, and wherein, described mental sickness is bipolar disorder.
17. according to claim 13ly prevent and/or treat method, and wherein, described mental sickness is eating disorders.
18. according to claim 13ly prevent and/or treat method, and wherein, described mental sickness is attention deficit hyperactivity disorder.
19. according to claim 13ly prevent and/or treat method, and wherein, described mental sickness is anxiety disorder.
20. according to claim 19ly prevent and/or treat method, and wherein, described anxiety disorder is obsession.
21. according to claim 19ly prevent and/or treat method, and wherein, described anxiety disorder is posttraumatic stress disorder.
22. according to preventing and/or treating method in claim 1 to 21 described in any one, wherein, patient can not obtain for the behavioral and psychiatric symptoms relevant to neurodegenerative disease or the effect of impulsion symptom abundance of being correlated with mental sickness from the medicine of usually available antipsychotic drug or neurodegenerative disease.
23. according to claim 22ly prevent and/or treat method, wherein, described usually available antipsychotic drug is chlorpromazine, fluphenazine, levomepromazine, perphenazine, periciazine, bromperidol, haloperidol, pipamperone, timiperone, nemonapride, sulpiride, sultopride, carpipramine, clocapramine, mosapramine, pimozide, oxypertine, zotepine, amisulpride, risperidone, iloperidone, cis-N-[4-[4-(1,2-Benzisothiazol-3-yl)-1-piperazinyl, 9-hydroxy-risperidone, Lurasidone, Ziprasidone, asenapine, clozapine, olanzapine, Quetiapine, blonanserin, Aripiprazole, the vertical piperazine of card or Sertindole, or their salt.
24. according to claim 22ly prevent and/or treat method, wherein, the medicine of described usually available neurodegenerative disease is donepezil, galantamine, Rivastigmine, memantine, FTY720, methylprednisolone, azathioprine, mitoxantrone, cyclophosphamide, interferon-β preparation, lattice draw for thunder, teriflunomide or natalizumab, or their salt.
25. 1 kinds prevent and/or treat agent for the behavioral and psychiatric symptoms relevant to neurodegenerative disease or the impulsion symptom of being correlated with mental sickness, and it contains 7-[4-(4-benzo [b] thiophene-4-base-piperazine-1-base) butoxy]-1H-quinoline-2-one-or its salt as effective ingredient.
26. according to claim 25ly prevent and/or treat agent, and it is prevent and/or treat agent for the behavioral and psychiatric symptoms relevant to neurodegenerative disease.
27. according to claim 25ly prevent and/or treat agent, and it is prevent and/or treat agent for the impulsion symptom relevant to mental sickness.
28. according to claim 26ly prevent and/or treat agent, and wherein, described neurodegenerative disease is selected from dementia, multiple sclerosis, parkinson's syndrome, juvenile stage parkinson disease, striatonigral degeneration, Progressive symmetric erythrokeratodermia core is benumbed, motion can not completely, prion disease, cortical basal ganglionic degeneration, chorea acanthocytosis, optimum heritability chorea, paroxysmal choreoathetosis, essential tremor, essential myoclonus, gilles de la Tourette syndrome, Rett syndrome, degeneration ballism, dystonia musculorum deformans, athetosis, spasmodic torticollis, the hot syndrome of prunus mume (sieb.) sieb.et zucc., cerebral palsy, hepatolenticular degeneration, rapids Chuan Shi is sick, Ha-Shi syndrome, neural axon malnutrition, pallidal atrophy, spinocerebellar degeneration, cerebral cortical atrophy, Holmes type cerebellar atrophy, olivopontocerebellar atrophy, heritability olivopontocerebellar atrophy, Joseph disease, dentatorubropallidoluysian atrophy, Ge-Shi-Sha syndrome, Friedreich ataxia, Lu-Lai syndrome, Mei-Huai syndrome, congenital cerebellar ataxia, periodically hereditary ataxia, Ataxia telangiectasia, amyotrophic lateral sclerosis, progressive bulbar palsy, myelopathic muscular atrophy, spinobulbar muscular atrophy, Wei-Huo is sick, Ku-Wei is sick, hereditary spastic paraplegia, syringomyelia, syringobulbia, A-Xi deformity, stiff man syndrome, Ke-Fei syndrome, Fazio-Londe disease, low myelopathy, Dan-Wo syndrome, spina bifida, She-La syndrome, radiation myelopathy, age-related macular degeneration, and the apoplexy to cause due to cerebral hemorrhage and/or relative dysfunction or neurological deficit.
29. according to claim 28ly prevent and/or treat agent, and wherein, described neurodegenerative disease is dull-witted.
30. according to claim 29ly prevent and/or treat agent, and wherein, described dementia is dementia of the Alzheimer type.
31. according to claim 29ly prevent and/or treat agent, and wherein, described dementia is dementia with Lewy body.
32. according to claim 29ly prevent and/or treat agent, and wherein, described dementia is Frontotemporal dementia.
33. according to claim 29ly prevent and/or treat agent, and wherein, described dementia is vascular dementia.
34. according to claim 29ly prevent and/or treat agent, and wherein, described dementia is that Parkinson is dull-witted.
35. according to claim 29ly prevent and/or treat agent, and wherein, described dementia is Huntington Chorea.
36. according to claim 28ly prevent and/or treat agent, and wherein, described neurodegenerative disease is multiple sclerosis.
37. according to claim 27ly prevent and/or treat agent, wherein, described mental sickness is selected from schizophrenia, refractory schizophrenia, refractory schizophrenics, chronic schizophrenia, dysthymic disorder, mental disorder, mood disorders, bipolar disorder, mania, depression, endogenous depression, major depression, melancholic and refractory depression, dysthymic disorder, circular type's affective disorder, anxiety disorder, somatic disturbance, do factitious disorder, dissociative disorder, sexual disorders, eating disorders, sleep disorder, adjustment disorder, Substance-related disorders, anhedonia, delirium, vomiting, motion sickness, obesity, migraine, pain, mental retardation, autism, tourette's disorder, Tic disorders, attention deficit hyperactivity disorder, conduct disorder, intermittent explosive disorder, kleptomania, pyromania, Pathological Gambling, trichotillomania, mongolism and personality disorder.
38. prevent and/or treat agent according to according to claim 37, and wherein, described mental sickness is selected from schizophrenia, refractory schizophrenia, refractory schizophrenics and chronic schizophrenia.
39. prevent and/or treat agent according to according to claim 37, and wherein, described mental sickness is selected from depression, endogenous depression, major depression, melancholic and refractory depression.
40. prevent and/or treat agent according to according to claim 37, and wherein, described mental sickness is bipolar disorder.
41. prevent and/or treat agent according to according to claim 37, and wherein, described mental sickness is eating disorders.
42. prevent and/or treat agent according to according to claim 37, and wherein, described mental sickness is attention deficit hyperactivity disorder.
43. prevent and/or treat agent according to according to claim 37, and wherein, described mental sickness is anxiety disorder.
44. according to claim 43ly prevent and/or treat agent, and wherein, described anxiety disorder is obsession.
45. according to claim 43ly prevent and/or treat agent, and wherein, described anxiety disorder is posttraumatic stress disorder.
46. according to preventing and/or treating agent in claim 25 to 45 described in any one, and it for not obtaining for the behavioral and psychiatric symptoms relevant to neurodegenerative disease or the treatment of the patient of the effect of impulsion symptom abundance of being correlated with mental sickness from the medicine of usually available antipsychotic drug or neurodegenerative disease.
47. according to claim 46ly prevent and/or treat agent, wherein, described usually available antipsychotic drug is chlorpromazine, fluphenazine, levomepromazine, perphenazine, periciazine, bromperidol, haloperidol, pipamperone, timiperone, nemonapride, sulpiride, sultopride, carpipramine, clocapramine, mosapramine, pimozide, oxypertine, zotepine, amisulpride, risperidone, iloperidone, cis-N-[4-[4-(1,2-Benzisothiazol-3-yl)-1-piperazinyl, 9-hydroxy-risperidone, Lurasidone, Ziprasidone, asenapine, clozapine, olanzapine, Quetiapine, blonanserin, Aripiprazole, the vertical piperazine of card or Sertindole, or their salt.
48. according to claim 46ly prevent and/or treat agent, wherein, the medicine of described usually available neurodegenerative disease is donepezil, galantamine, Rivastigmine, memantine, FTY720, methylprednisolone, azathioprine, mitoxantrone, cyclophosphamide, interferon-β preparation, lattice draw for thunder, teriflunomide or natalizumab, or their salt.
49.7-[4-(4-benzo [b] thiophene-4-base-piperazine-1-base) butoxy]-1H-quinoline-2-one-or its salt are for the production of the behavioral and psychiatric symptoms relevant to neurodegenerative disease or the purposes preventing and/or treating agent of impulsion symptom of being correlated with mental sickness.
50. for the behavioral and psychiatric symptoms relevant to neurodegenerative disease or 7-[4-(4-benzo [b] thiophene-4-base-piperazine-1-base) the butoxy]-1H-quinoline-2-one-prevented and/or treated of impulsion symptom of being correlated with mental sickness or its salt.
51. 1 kinds for the behavioral and psychiatric symptoms relevant to neurodegenerative disease or the pharmaceutical composition prevented and/or treated of impulsion symptom of being correlated with mental sickness, it comprises 7-[4-(4-benzo [b] thiophene-4-base-piperazine-1-base) butoxy]-1H-quinoline-2-one-or its salt as effective ingredient.
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